Is MYO7A p.Ala1755Val (c.5264C>T) pathogenic?

MYO7A p.Ala1755Val (c.5264C>T) is classified Conflicting classifications of pathogenicity in MYO7A (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-26). AlphaMissense: ambiguous (0.3887); Ultra-rare (popmax 0.0451%, mid); Associated with MYO7A-related disorder.

What condition is associated with MYO7A p.Ala1755Val (c.5264C>T)?

MYO7A p.Ala1755Val (c.5264C>T) is associated with MYO7A-related disorder, Usher syndrome type 1B (ClinVar).

How common is MYO7A p.Ala1755Val (c.5264C>T) in the general population?

MYO7A p.Ala1755Val (c.5264C>T) is ultra-rare (popmax 0.0451%, mid) (gnomAD).

What do computational predictors say about MYO7A p.Ala1755Val (c.5264C>T)?

AlphaMissense predicts ambiguous (score 0.3887) — an in-silico prediction, not a clinical call.

MYO7A p.Ala1755Val

c.5264C>T · rs574917232 · VCV229008

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MYO7A-related disorder

Computational evidence

Protein change
AlphaMissense	0.3887	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -8.19	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.24	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0451% Middle Eastern · 2/4,436 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00805%

Overall 0.00509% 79/1,551,178 alleles · ultra-rare exomes 74/1,398,824 · genomes 5/152,354 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0451%	2,218
Admixed American	0.0195%	5,124
South Asian	0.0119%	8,406
Remaining individualsnot grpmax-eligible	0.00666%	15,011
European (non-Finnish)	0.00427%	23,431
African / African-American	0.0041%	24,409
Finnishnot grpmax-eligible	0.00168%	59,364

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Ala1755Val
Coding: c.5264C>T
MANE Select: NM_000260
dbSNP: rs574917232
Type: single nucleotide variant
Location: chr11:77203155 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1755: the myth4 2 domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MYO7A-related disorder

Also linked: Usher syndrome type 1B

Similar variants

MYO7A p.Ala1755Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MYO7A p.Ala1755Ser Uncertain significance ★★ ⚠ same residue
MYO7A p.Ala1755= Likely benign ★ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
MYO7A p.Arg668Cys Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-ala1755val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown